Engineering polymeric micelles for targeted drug delivery: “click” chemistry enabled bioconjugation strategies and emerging applications

In recent years, there has been remarkable progress in designing drug delivery systems since the dawn of polymer therapeutics. Advances in polymer science and bioconjugation chemistry continue to advance the design and efficiency of drug delivery systems. Among the various drug delivery systems, polymeric micelles stand out because of their versatile features, like increased bioavailability of hydrophobic therapeutic cargo, as well as enhanced uptake in tumors because of their nanosize-mediated passive targeting. Importantly, the polymeric micelles can be engineered to actively target disease sites through surface functionalization with appropriate bioactive ligands. Decorating the micelle surface with bioactive ligands has emerged as one of the most preferred approaches to enhance their targeting capability. Over the years, many ligands have been explored for active targeting, ranging from sugars and peptides to antibodies and oligonucleotides. Progress in protein sciences and molecular biology continues to reveal new ligands and enlarge this library. Considering the delicate nature of the biological ligands, the utilization of mild, efficient, and benign chemical transformations is vital. In this context, the advent of "click" chemistry has dramatically altered the design of targeted micelles. The ability to modify polymers with "clickable" handles at the desired locations, as well as control over the density of these reactive units, expands the utilization of this chemistry. Over the years, the focus has shifted from the highly efficient copper-catalyzed azide-alkyne cycloaddition to "metal-free click" reactions. Additionally, bioorthogonal "click" reactions have enabled the achievement of "in vivo click" transformation-based targeting strategies either through metabolic glycoengineering or stimuli-induced aggregation. This review focuses on the advances in the fabrication of ligand-based targeted micelles using the "click" reaction for ligand conjugation onto polymeric micelles and highlights recent applications of these materials for targeted drug delivery.